New 3 '-azido-3 '-deoxythymidin-5 '-yl O-(4-hydroxyalkyl or -alkenyl or -alkylepoxide) carbonate prodrugs: Synthesis and anti-HIV evaluation

New 5 ' -O-carbonate prodrugs of zidovudine (AZT) have been synthesized in order to enhance its uptake by HIV-1 infected cells, to improve its anti-HI V potency, and to optimize the intramolecular cyclic rearrangement process related to the 5 ' -O-(4-hydroxybutyl) carbonate moiety. Evidence of this p rodrug rearrangement was confirmed by comparison of the serum half-lives of the 3 ' -azido-3 ' -deoxythymidin-5 ' -yl O-(4-hydroxyalkyl or -alkenyl or -alkylepoxide) carbonate prodrugs with our thermodynamic predictions. Inte restingly, these 5 ' -O-carbonate prodrug series show increased anti-HIV po tencies in conjunction with, or without, reduced cytotoxicity as compared t o AZT that lead to a gain in selectivity indexes. The cytotocity of AZT cou ld be reduced with these 5 ' -O-carbonate prodrug series by delaying the 5 ' -O-glucuronidation of AZT, which is one of the major limitations of AZT.